title: Carboxypeptidase E protects hippocampal neurons during stress in male mice by up-regulating prosurvival BCL2 protein expression.
abstract: Prolonged chronic stress causing elevated plasma glucocorticoids leads to neurodegeneration. Adaptation to stress (allostasis) through neuroprotective mechanisms can delay this process. Studies on hippocampal neurons have identified carboxypeptidase E (CPE) as a novel neuroprotective protein that acts extracellularly, independent of its enzymatic activity, although the mechanism of action is unclear. Here, we aim to determine if CPE plays a neuroprotective role in allostasis in mouse hippocampus during chronic restraint stress (CRS), and the molecular mechanisms involved. Quantitative RT-PCR/in situ hybridization and Western blots were used to assay for mRNA and protein. After mild CRS (1 h/d for 7 d), CPE protein and mRNA were significantly elevated in the hippocampal CA3 region, compared to naïve littermates. In addition, luciferase reporter assays identified a functional glucocorticoid regulatory element within the cpe promoter that mediated the up-regulation of CPE expression in primary hippocampal neurons following dexamethasone treatment, suggesting that circulating plasma glucocorticoids could evoke a similar effect on CPE in the hippocampus in vivo. Overexpression of CPE in hippocampal neurons, or CRS in mice, resulted in elevated prosurvival BCL2 protein/mRNA and p-AKT levels in the hippocampus; however, CPE(-/-) mice showed a decrease. Thus, during mild CRS, CPE expression is up-regulated, possibly contributed by glucocorticoids, to mediate neuroprotection of the hippocampus by enhancing BCL2 expression through AKT signaling, and thereby maintaining allostasis.
authors.affiliation: Section on Cellular Neurobiology, Program on Developmental Neuroscience, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: S R K
authors.initials: SR
authors.lastname: Murthy
authors.forename: E
authors.initials: E
authors.lastname: Thouennon
authors.forename: W-S
authors.initials: WS
authors.lastname: Li
authors.forename: Y
authors.initials: Y
authors.lastname: Cheng
authors.forename: J
authors.initials: J
authors.lastname: Bhupatkar
authors.forename: N X
authors.initials: NX
authors.lastname: Cawley
authors.forename: M
authors.initials: M
authors.lastname: Lane
authors.forename: I
authors.initials: I
authors.lastname: Merchenthaler
authors.forename: Y P
authors.initials: YP
authors.lastname: Loh
mesh_terms: D052636:Allostasis; D000818:Animals; D056654:CA3 Region, Hippocampal / Q000378:metabolism / Q000473:pathology; D043423:Carboxypeptidase H / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000166:cytology; D017930:Genes, Reporter / Q000187:drug effects; D005938:Glucocorticoids / Q000378:metabolism / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D011401:Promoter Regions, Genetic / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000378:metabolism; D012149:Restraint, Physical; D012720:Severity of Illness Index; D013312:Stress, Physiological; D013315:Stress, Psychological / Q000378:metabolism* / Q000503:physiopathology; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D005938:Glucocorticoids; D009419:Nerve Tissue Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011994:Recombinant Proteins; C052617:Bcl2 protein, mouse; D043423:Carboxypeptidase H